The present invention relates to a bioavailable pharmaceutical composition of 13-cis vitamin A acid (also known as 13-cis retinoic acid and isotretinoin) and a process for preparing the same. 13-cis vitamin A acid is a relatively water insoluble compound that degrades when exposed to light and atmospheric oxygen. Due to its instability and relative insolubility, the bioavailability of the drug after oral administration is difficult to achieve and has always been a challenge to a development pharmacist. It would therefore be desirable to provide a dosage form in which the drug is stable and predictably bioavailable.
U.S. Pat. No. 4,464,394 assigned to Hoffman LaRoche Inc. discloses compositions and methods of using 13-cis vitamin A acid against the development of epithelial carcinomas of the skin, gastrointestinal tract, respiratory tract or genito-urinary tract. However, only a general description of the composition is given in this patent and no data on the bioavailability of the active ingredient in the composition is disclosed.
European Patent No. 184942 assigned to Ortho Pharmaceutical Corp. discloses pharmaceutical compositions having not more than 22% wax content which is a critical limitation of this patent, as higher wax content tends to diminish the bioavailability. The particle size of the drug is also reduced to less than 12 xcexcm prior to its incorporation into the formulation. Said objectives of the bioavailability are achieved by controlling the particle size and the wax content. As 13-cis vitamin A may cause decreased night vision and corneal opacities at higher concentrations, its micronization in the powder state can be hazardous as this involves a lot of dry powder handling. Further, handling of isotretinoin at room temperature under atmospheric oxygen can lead to its degradation, as it is a highly unstable drug.
It is an object of the present invention to solve the problems associated with the prior art and to provide a process which uses conditions that are convenient to perform on a commercial scale and are operationally safe.
More particularly, the present invention relates to a process of making bioavailable capsule formulation of 13-cis vitamin A acid comprising the steps of (a) mixing the drug with the carrier to form the medicament paste (b) milling the medicament paste to achieve a particle size less than 300 xcexcm, and (c) mixing the milled medicament paste with the suspending agent, and optionally with carrier material and other pharmaceutically acceptable excipients.
It is observed that the particle size is critical in achieving the bioequivalence against the commercially available marketed formulation of isotretinoin sold under the trade name of xe2x80x9cAccutanexe2x80x9d. In preferred embodiments of the invention, the particle size of 13-cis vitamin A acid in the medicament paste is less than 275 xcexcm. The surface area of the drug in the medicament paste varies between 0.05-0.3 sq m/g. The medicated paste is milled using any of the conventionally known techniques, such as ball mill, colloid mill etc.
The carrier material used in accordance with the present invention may be selected from the group consisting of peanut oil, soyabean oil, sesame oil, mineral oil, cotton seed oil, polyethylene glycol and mixtures thereof.
The suspending agent used in accordance with the present invention is a wax mixture comprising 1 part hydrogenated soyabean oil, 1.2 parts white wax and 4.2 parts hydrogenated vegetable oil. The suspending agent is used in amounts of more than 30% of the formulation. More preferably, the suspending agent is used in amounts between 30-40% w/w of the formulation.
The formulation of the present invention may further contain suitable pharmaceutical excipients such as anti-oxidants and chelating agents.
The anti-oxidant employed in the present invention may be selected from the group consisting of xcex1-tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbyl palmitate and propyl gallate. Chelating agents may be chosen amongst disodium edetate and calcium disodium edetate.
Investigations were conducted in order to determine the effect of particle size on the bioavailability of 13-cis vitamin A acid in the formulations of this invention. The blood levels of the drug were compared with that of the commercially available formulation of 13-cis vitamin A acid sold as a soft gelatin capsule, under the trade name of xe2x80x9cAccutanexe2x80x9d. The area under the plasma concentration (13-cis vitamin A acid) vs. time curve (AUC) was determined between time xe2x80x9c0xe2x80x9d and time xe2x80x9ctxe2x80x9d to give the AUC(0-t) values and was then extrapolated to infinity (∞) to calculate the value till there was no more drug in the plasma. This value is reported as AUC(0-∞). The maximum plasma concentration (Cmax) was also determined for each subject after each treatment.
The following examples further illustrate the invention but are not intended to limit the scope of the invention.
Soft gelatin capsules were prepared as described in Table 1.
Isotretinoin was mixed with soyabean oil to form a 25% dispersion or medicated paste. The medicated paste was milled and the particle size of the drug in the paste following milling was determined. The remaining amount of the carrier material (soyabean oil), wax mixture and other ingredients were then added to the milled medicated paste and mixed with stirring. The formulation so prepared was used to study the effect of particle size on the bioavailability of the drug keeping all the other formulation parameters constant.